Few objective criteria have been validated for serial clinical monitoring in patients with cystic fibrosis (CF) during pulmonary exacerbations. While pulmonary function tests (PFT) are often used to monitor clinical improvement, it is not known which test correlates most closely with clinical improvement. To answer this, we measured routine PFT in 58 patients with CF before, during, and at discharge after 2-3 week hospital admission in 71 episodes of pulmonary exacerbation. Patients with CF were discharged based on clinical, radiological, and laboratory criteria. In general, all PFTs improved at midadmission and improved further by discharge, at which time forced expiratory volume in 1 second (FEV1), forced expiratory flow between 25% and 75% of forced vital capacity (FEF25-75), vital capacity (VC), maximal voluntary ventilation (MVV), and oxygen saturation by pulse oximetry (SPO2) increased. The residual volume to total capacity ratio (RV/TLC) and the slope of phase 3 in the single breath N2 washout curve (SP3 N2) decreased. The change in SP3 N2 was significantly greater than in any other PFT (P < 0.01 vs. VC and FEV1; P < 0.02 vs. RV and P < 0.001 vs. SPO2). A calculated optimal cut-off value for SP3 N2 improvement was significantly more sensitive in identifying patient improvement at discharge than any other pulmonary function test (P = 0.005). We speculate that clinical improvement in patients with CF is closely linked to improved distribution of ventilation.